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Article

Total Synthesis of the Proposed Structure of Indolyl 1,2-Propanediol Alkaloid, 1-(1H-Indol-3-yloxy)propan-2-ol

by
Momoko Kimata
and
Takumi Abe
*
Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama City 700-8530, Japan
*
Author to whom correspondence should be addressed.
Chemistry 2023, 5(4), 2772-2784; https://doi.org/10.3390/chemistry5040177
Submission received: 10 November 2023 / Revised: 9 December 2023 / Accepted: 11 December 2023 / Published: 12 December 2023
(This article belongs to the Section Biological and Natural Products)
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Abstract

:
The first total synthesis of the proposed structure of unprecedented indolyl derivative bearing 1,2-propanediol moiety is described. Isomerization of 3-alkoxyindolines through indolenium intermediates was the key step in the total synthesis. 1H, 13C-NMR, IR, and HRMS spectra of the synthetic compound drastically differed to those of the originally reported structure, which suggests the natural product requires revision.

Graphical Abstract

1. Introduction

Alkoxyindoles are privileged structures that are found in natural products, which exhibit significant biological activities and are interesting targets for organic chemistry [1]. For example, koniamborine, isolated from Boronnella koniambiensis aerial parts, shows significant cytotoxicity against the L1210 cancer cell line [2]. Cladoniamide G, isolated from cultures of Streptomyces uncialis, is also cytotoxic to MCF-7 cells in vitro at 10 mg/mL [3]. Pyrrolidinoindoline-type alkaloid CPC-1 was isolated from the seeds and rinds of Chimonanthus praecox f. concolor [4]. Oxytrofalcatins A-F and 3-oxygenated N-benzoyl indole analogs from the roots of Oxytropis falcata (Leguminosae) were revised to 2,5-diaryloxazoles by Abe and Yamada [5,6]. Isolated natural products represent a valuable resource of pharmaceutical reagents [7], such as the 5-HT4 antagonist [8], antiproliferative agents [9], and VATPase inhibitors [10]. Therefore, developing concise routes for oxygenated indoles is of great significance. Although there are indirect methods to access such oxygenated indoles [11,12,13,14,15,16,17,18], many efforts have been made toward direct oxy-functionalization at C2 or C3 positions in indolines or indoles [19,20,21,22]. In 2000, Kettle and coworkers reported that rhodium(II)-catalyzed O–H insertion reactions of 2-carboethoxy-3-diazo-3H-indole to generate high 3-alkoxyindole yields [23]. Zhang’s group presented a direct approach to C3-acetoxylated biindolyls via palladium catalysis using AgOAc under oxygen atmosphere as oxidants [24]. In contrast to the vast majority of metal-catalyzed synthesis approaches for oxygenated indoles [25,26,27,28,29,30,31,32,33,34,35], metal-free approaches have emerged as powerful synthetic tools owing to their sustainable properties [36,37,38,39,40,41,42,43,44,45,46,47]. However, these reactions are limited to the construction of either C2-oxygenated or C3-oxygenated indole/indoline. Given the difficulty of switchable construction for oxygenated indole/indoline, we recently reported the regioselective synthesis of both 2- and 3-alkoxyindoles from the common intermediate, 2-alkoxy-3-bromoindolines (ROBIN) [48]. The synthesis of 2-alkoxyindoles was achieved by a base-mediated regioselective elimination of HBr from ROBIN. In other hands, 3-alkoxyindoles were obtained by silver-mediated alkoxylation followed by the BF3•OEt2-promoted elimination of alkoxide at the C3-position of the indole ring.
1-(1H-Indol-3-yloxy)propan-2-ol (1) is an indolyl derivative isolated from the Red Sea sponge Haliclona sp. and was published in 2016 by Al-Massarani and co-workers (Figure 1) [49]. Structurally, 1-(1H-Indol-3-yloxy)propan-2-ol (1) differs from previously reported alkoxyindoles [1,2,3,4,5,6,7,8,9]. It has an unprecedented 1,2-propandiol moiety at the C3 position of indole. Furthermore, 1,2-propandiol possesses anti-microbial activity, and is used as a preservative agent in pharmaceuticals and food [50].
Potential biological activity in combination with unprecedented indolyl saccharide bearing 1,2-propandiol makes 1-(1H-indol-3-yloxy)propan-2-ol (1) an attractive synthetic target for medicinal and synthetic chemistry. However, the structure of 1 was determined by 2D-NMR and MS analyses, while neither of its [α]D data nor absolute configurations were presented. Furthermore, the reported 1H-NMR spectrum of 1 in CD3OD showed a resonance at 7.95 ppm (H-2), which was too low a field shift for 3-alkoxyindoles. These inconsistencies suggest that organic synthesis is needed to confirm the structure, including the absolute configuration of 1. Based on our interest in 3-alkoxyindoles, the determination of the real 1 structure is worth investigating. Herein, we report the total synthesis of the proposed structure of 1 starting from N-tosylindole (2).

2. Materials and Methods

High-resolution MS spectra were recorded with a Brucker micrOTOF mass spectrometers (ESI-TOF-MS). NMR experiments were performed with a JEOL JNM-ECZ600R (1H NMR: 600 MHz, 13C NMR: 151 MHz) spectrometer, a Varian 600-MR ASW (1H NMR: 600 MHz, 13C NMR: 151 MHz) spectrometer, and a Varian 400-MR ASW (1H NMR: 400 MHz, 13C NMR: 100 MHz) spectrometer, with chemical shifts expressed in ppm (δ) using residual undeuterated solvent as an internal reference. 1H NMR spectra were referenced to tetramethylsilane as an internal standard or to a solvent signal (CDCl3: 7.26 ppm, methanol-d6: 3.31 ppm, DMSO-d6: 2.50 ppm). 13C NMR spectra were referenced to a solvent signal (CDCl3: 77.1 ppm, methanol-d6: 49.00 ppm, DMSO-d6: 39.52 ppm). The following abbreviations were used to explain NMR peak multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, sep = septet, m = multiplet, dd = doublet of doublets, ddd = doublet of doublet of doublets, br = broad; coupling constants in Hz; integration. Reactions were monitored by thin layer chromatography (TLC) carried out on a silica gel plates (60F-254) and visualized under UV illumination at 254 or 365 nm depending on compounds. Flash column chromatography was performed on silica gel (WAKO Gel 75–150 mesh, WAKO Co., Ltd., Tokyo, Japan). All substrates were used as received from commercial suppliers (Sigma-Aldrich, Tokyo, Japan; Kanto Chemical, Tokyo, Japan; TCI, Tokyo, Japan; and Wako, Tokyo, Japan) and all reagents were weighed and handled in air at room temperature. All work-up and purification steps were carried out with reagent-grade solvents in air.

2.1. Synthesis of N-Tosylindoles (2) [51]: N-Tosylindoles (2) Was Prepared by a Reported Method [50]

1H NMR (400 MHz, CDCl3) δ: 8.00 (ddd, J = 8.3, 1.8, 1.2 Hz, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 3.6 Hz, 1H), 7.53 (ddd, J = 7.7, 1.2, 0.8 Hz, 1H), 7.32 (ddd, J = 8.2, 7.2, 1.2 Hz, 1H), 7.23 (ddd, J = 7.6, 6.8, 1.2 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 6.66 (dd, J = 3.6, 0.8 Hz, 1H), 2.34 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 144.9, 135.3, 134.8, 130.7, 129.8, 126.8, 126.3, 124.5, 123.2, 121.3, 113.5, 109.0, 21.5.

2.2. Synthesis of Trans-3-Bromo-2-methoxy-1-tosylindoline (ROBIN) [48]

To generate a solution of 2 (2.71 g, 10 mmol) in MeOH (100 mL, 0.1 M), we added NBS (1.96 g, 11 mmol). The mixture was stirred at room temperature for 2 h. After filtration, ROBIN was obtained as a crystal; 3.26 g, 85% yield; White crystal; 1H NMR (400 MHz, CDCl3) δ: 7.70 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.0 Hz, 1H), 7.34 (ddd, J = 7.8, 7.8, 1.2 Hz, 1H), 7.28 (ddd, J = 7.8, 1.4, 0.8 Hz, 1H), 7.20 (d, J = 8.8 Hz, 2H), 7.11 (ddd, J = 7.6, 7.6, 0.8 Hz, 1H), 5.59 (s, 1H), 4.95 (s, 1H), 3.61 (s, 3H), 2.34 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 144.5, 140.5, 135.1, 131.3, 130.5, 129.5, 127.7, 126.1, 125.3, 116.9, 99.8, 56.3, 47.1, 21.5.
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Analytical data are in accordance with literature values.

2.3. Synthesis of 5 and 6

To a solution of ROBIN (3.82 g, 10 mmol), propane-1,2-diol (3.7 mL, 50 mmol) in DCM (50 mL, 0.2 M) was added to Ag2O (2.32 g, 10 mmol) and AgOTf (128.5 mg, 0.50 mmol). The mixture was stirred at room temperature for 14 h. After filtration and concentrated in vacuo, the residue was purified by silica gel column chromatography (AcOEt/hexane = 1/10–1/1) to generate a mixture of 5 and 6 (5:6 = 1.0:1.9). 3.02 g, 80% yield; Orange oil.
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Analytical samples 5 and 6 were obtained by TBS protection and separated by silica gel column chromatography.

2.3.1. Synthesis of Trans-3-((1-tert-Butyldimethylsilyloxy)propan-2-yloxy)-2-methoxy-1-tosylindoline (TBS-5)

To a solution of a mixture of 5 and 6 (3.33 g, 8.8 mmol, 5:6 = 1:1.7) and imidazole (236.5 mg, 3.5 mmol) in DCM (60 mL, 0.15 M), we added TBSCl (498.4 mg, 3.3 mmol). The mixture was stirred at room temperature for 18 h. After filtration, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (AcOEt/hexane = 1/5–1/1) to generate TBS-5 (dr = 1.2:1). 523.7 mg, 12% yield; Yellow oil; IR (KBr): 1358, 1169, 1101 cm−1; 1H NMR (400 MHz, CDCl3) δ: 7.68 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.61–7.59 (m, 1H), 7.33–7.27 (m, 2H), 7.15–7.11 (m, 2H), 7.09–7.03 (m, 1H), 5.42 (s, 0.52H), 5.33 (s, 0.37 H), 4.73 (s, 0.41H), 4.58 (s, 0.48H), 3.72–3.64 (m, 1H), 3.601, 3.598 (2s, 3H), 3.52–3.28 (m, 2H), 2.32, 2.31 (2s, 3H), 1.04 (d, J = 7.2 Hz, 1.04H), 0.92 (d, J = 8.0 Hz, 1.53H), 0.94, 0.89 (2s, 9H), 0.11, 0.04, 0.03 (3s, 6H); 13C NMR (151 MHz, CDCl3) δ: 143.9, 143.8, 141.72, 141.65, 135.4, 135.3, 131.1, 130.9, 130.3, 130.2, 129.4, 129.3, 127.9, 127.6, 126.64, 126.60, 124.7, 124.6, 117.1, 116.9, 98.2, 97.8, 81.4, 81.2, 75.3, 74.9, 67.09, 67.05, 56.0, 55.9, 26.0, 25.9, 21.56, 21.54, 18.5, 18.3, 17.7, 17.2, −5.25, −5.27, −5.32, −5.42; HRMS (ESI) m/z: 514.2059 (Calcd for C25H37NNaO5SSi [M + Na]+: 514.2059).
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2.3.2. Synthesis of 2-(Trans-2-methoxy-1-tosylindolin-3-yloxy)propan-1-ol (5)

To a solution of TBS-5 (267.0 mg, 0.54 mmol) in THF (3.6 mL, 0.15 M), we added TBAF in THF (1.1 mL, 1.1 mmol). The mixture was stirred at room temperature for 1.5 h. The reaction mixture was quenched with saturated NH4Cl (10 mL) and extracted with AcOEt (3 × 10 mL). The organic extract was washed with brine (10 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (AcOEt/hexane = 1/1) to generate 5 (dr = 1.5:1). 124.7 mg, 61% yield; Yellow oil; IR (KBr): 1352, 1167, 1111, 1090, 999 cm−1; 1H NMR (400 MHz, CDCl3) δ: 7.69 (t, J = 8.0 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.36 (tt, J = 8.0, 1.6 Hz, 1H), 7.27 (dd, J = 7.4, 0.8 Hz, 1H), 7.18–7.16 (m, 2H), 7.13–7.08 (m, 1H), 5.31 (s, 0.6H), 5.26 (s, 0.38H), 4.53 (s, 0.57H), 4.47 (s, 0.37H), 3.78–3.63 (m, 1H), 3.60, 3.59 (2s, 3H), 3.45 (dd, J = 11.8, 3.6 Hz, 0.50H), 3.31–3.26 (m, 1H), 3.07 (dd, J = 11.6, 6.8 Hz, 0.39H), 2.34, 2.33 (2s, 3H), 1.11 (d, J = 6.0 Hz, 1.20H), 1.03 (d, J = 6.4 Hz, 1.90H); 13C NMR (101 MHz, CDCl3) δ: 144.4, 144.3, 141.8, 141.7, 135.3, 135.1, 131.0, 130.6, 130.5, 130.4, 129.5, 129.2, 127.5, 127.4, 126.5, 126.3, 125.0, 124.9, 117.7, 117.2, 98.2, 97.4, 80.7, 80.4, 74.84, 74.79, 66.1, 66.0, 56.04, 55.96, 21.5, 21.4, 16.0, 15.9; HRMS (ESI) m/z: 400.1195 (Calcd for C19H23NNaO5S [M + Na]+: 400.1195).
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2.3.3. Synthesis of 1-(Trans-2-Methoxy-1-tosylindolin-3-yloxy)propan-2-ol (TBS-6)

To a solution of a mixture of 5 and 6 (3.91 g, 10 mmol, 5:6 = 1:1.8) and imidazole (444.6 mg, 6.5 mmol) in DCM (65 mL, 0.15 M), we added TBSCl (937.4 mg, 6.2 mmol). The mixture was stirred at room temperature for 19 h. After filtration, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (AcOEt/hexane = 1/5–1/1) to generate TBS-6 (dr = 1.3:1). 2.23 g, 58% yield; Yellow oil; IR (KBr): 1358, 1167, 1109, 1084, 1022 cm−1; 1H NMR (400 MHz, CDCl3) δ: 7.67 (d, J = 7.6 Hz 1H), 7.59 (d, J = 7.6 Hz, 2H), 7.34 (t, J = 7.6 Hz, 1H), 7.27 (s, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.07 (t, J = 7.6 Hz, 1H), 5.31, 5.29 (2s, 1H), 4.37 (s, 1H), 3.57 (s, 3H), 3.57–3.53 (m, 1H), 3.36 (dd, J = 8.8, 2.4 Hz, 0.54 H), 3.28 (dd, J = 8.6, 2.8 Hz, 0.42H), 3.21–3.15 (m, 1H), 0.99 (2d, J = 6.0, 4.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 144.3, 144.2, 141.83, 141.76, 135.23, 135.20, 130.57, 130.55, 130.2, 130.1, 129.35, 129.32, 127.41, 127.40, 126.71, 126.70, 124.79, 124.72, 117.46, 117.41, 96.9, 96.8, 82.9, 82.8, 74.3, 74.1, 66.14, 66.10, 55.9, 21.43, 21.41, 18.41, 18.38; HRMS (ESI) m/z: 400.1195 (Calcd for C19H23NNaO5S [M + Na]+: 400.1195).
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2.4. Synthesis of 7 and 3

A mixture of 5 and 6 (113.2 mg, 0.30 mmol, 5:6 = 1:1.9) was dissolved in AcOEt/MeCN (3/1, 2.4 mL, 0.125 M). To this solution, we added BF3•Et2O (0.19 mL, 1.5 mmol) and the mixture was stirred at room temperature for 6 h. After addition of H2O, the mixture was extracted with AcOEt (3 × 10 mL) and washed with saturated NaHCO3 (10 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (AcOEt/hexane = 1/5–1/1) to generate a mixture of 7 and 3 (7:3 = 1:1.1). 52.1 mg, 50% yield; Yellow oil.
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Analytical sample 7 was obtained by TBS protection and separated by silica gel column chromatography.

2.4.1. Synthesis of 3-((1-tert-Butyldimethylsilyloxy)propan-2-yloxy)-1-tosyl-1H-indole (TBS-7)

To a solution of a mixture of 7 and 3 (965.5 mg, 2.8 mmol, 7:3 = 1:1.5) and imidazole (81.7 mg, 1.2 mmol) in DCM (19 mL, 0.15 M), we added TBSCl (168.8 mg, 1.1 mmol). The mixture was stirred at room temperature for 16 h. After filtration, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (AcOEt/hexane = 1/5–1/1) to generate TBS-7. 415.2 mg, 37% yield; Orange oil; IR (KBr): 1367, 1215, 1174, 1103 cm−1; 1H NMR (400 MHz, CDCl3) δ: 7.99 (ddd, J = 8.0, 0.8, 0.8 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.50 (ddd, J = 7.8, 1.2, 0.8 Hz, 1H), 7.32 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.20 (ddd, J = 8.0, 7.2, 0.8 Hz, 1H), 7.16 (d, J = 8.0 Hz, 2H), 6.92 (s, 1H), 4.26 (tq, J = 6.0, 2.8 Hz, 1H), 3.82 (dd, J =11.0, 5.6 Hz, 1H), 3.71 (dd, J = 10.6, 4.8 Hz, 1H), 2.32 (s, 3H), 1.34 (d, J = 6.0 Hz, 3H), 0.88 (s, 9H), 0.06, 0.02, 0.00 (3s, 6H); 13C NMR (101 MHz, CDCl3) δ:144.7, 144.5, 134.3, 129.8, 126.9, 125.7, 123.3, 118.9, 114.3, 105.6, 78.1, 66.1, 26.0, 21.7, 16.3, 0.14, −5.13, −5.20; HRMS (ESI) m/z: 482.1797 (Calcd for C24H33NNaO4SSi [M + Na]+: 482.1797).
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2.4.2. Synthesis of 1-(1-Tosyl-1H-indol-3-yloxy)propan-2-ol (7)

To a solution of TBS-7 (415.2 mg, 1.1 mmol) in THF (7.0 mL, 0.15 M), we added TBAF in THF (2.1 mL, 2.1 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated NH4Cl (10 mL) and extracted with AcOEt (3 × 10 mL). The organic extract was washed with brine (10 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (AcOEt/hexane = 1/5–1/1) to generate 7. 279.4 mg, 77% yield; Yellow oil; IR (KBr): 1363, 1213, 1173, 1101 cm−1; 1H NMR (400 MHz, CDCl3) δ: 8.00 (ddd, J = 8.4, 0.8, 0.8 Hz, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.51 (ddd, J = 8.0, 1.2, 0.8 Hz, 1H), 7.33 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.21 (ddd, J = 8.0, 7.2, 0.8 Hz, 1H), 7.17 (d, J = 8.0 Hz, 2H), 6.97 (s, 1H), 4.36 (tq, J = 6.0, 3.6 Hz, 1H), 3.79 (dd, J = 12.0, 3.6 Hz, 1H), 3.75 (dd, J = 12.0, 6.8 Hz, 1H), 2.31 (s, 3H), 1.32 (d, J = 6.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ:144.5, 143.6, 134.4, 133.8, 129.5, 126.5, 125.6, 125.1, 123.0, 118.3, 114.0, 105.8, 77.8, 65.8, 21.3, 15.2; HRMS (ESI) m/z: 368.0933 (Calcd for C18H19NNaO4S [M + Na]+: 368.0933).
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2.5. Synthesis of 2-(1-Tosyl-1H-indol-3-yloxy)propan-1-ol (3)

To a solution of a mixture of 7 and 3 (521.0 mg, 1.5 mmol, 7:3 = 1:1.1) and imidazole (52.9 mg, 0.77 mmol) in DCM (10 mL, 0.15 M), we added TBSCl (111.9 mg, 0.74 mmol). The mixture was stirred at room temperature for 18 h. After filtration, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (AcOEt/hexane = 1/5–1/1) to generate 3. 188.1 mg, 36% yield; Yellow oil; IR (KBr): 1362, 1215, 1173, 1120 cm−1; 1H NMR (400 MHz, CDCl3) δ: 8.00 (ddd, J = 8.4, 0.8, 0.8 Hz, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.52 (ddd, J = 7.8, 1.6, 0.8 Hz, 1H), 7.34 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.22 (ddd, J = 7.8, 7.2,1.2 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 6.92 (s, 1H), 4.26 (tq, J = 3.6, 3.2 Hz, 1H), 3.97 (dd, J = 9.4, 3.2 Hz, 1H), 3.84 (dd, J = 9.4, 8.0 Hz, 1H), 2.32 (s, 3H), 1.31 (d, J = 6.8, 3H); 13C NMR (101 MHz, CDCl3) δ:145.7, 145.2, 135.1, 134.5, 130.2, 127.2, 126.3, 124.9, 123.7, 118.9, 114.7, 105.1, 76.3, 66.6, 22.0, 19.2; HRMS (ESI) m/z: 368.0933 (Calcd for C18H19NNaO4S [M + Na]+: 368.0933).
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2.6. Synthesis of 1-(1H-Indol-3-yloxy)propan-2-ol (1)

To solution 3 (283.2 mg, 0.82 mmol) in DMSO (8.2 mL, 0.1 M), we added tBuOK (276.0 mg, 3.0 equiv.). The mixture was stirred at room temperature until the complete disappearance of starting material, as indicated by TLC. The reaction mixture was quenched with saturated NH4Cl (10 mL) and extracted with AcOEt (3 × 10 mL). The organic extract was washed with brine (10 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (AcOEt/hexane = 1/5–1/1) to generate 1. 40.2 mg, 26% yield. yellow oil. IR (KBr): 3419, 1558, 1234, 1101 cm−1; 1H NMR (600 MHz, Methanol-d4) δ: 7.57 (ddd, J = 7.8, 1.2, 1.2 Hz, 1H), 7.25 (ddd, J = 8.4, 0.6, 0.6 Hz, 1H), 7.08 (ddd, J = 8.1, 7.2, 1.2 Hz, 1H), 6.95 (ddd, J = 8.0, 7.2, 1.2 Hz, 1H), 6.80 (s, 1H), 4.17 (tq, J = 6.0, 5.4 Hz, 1H), 3.90 (dd, J = 5.7, 0.6 Hz, 2H), 1.30 (d, J = 6.0 Hz, 3H); 13C NMR (151 MHz, Methanol-d4) δ: 140.1, 134.5, 121.6, 119.4, 117.7, 117.1, 110.9, 105.5, 76.2, 65.9, 18.4; HRMS (ESI) m/z: 214.0844 (Calcd for C11H13NNaO2 [M + Na]+: 214.0844).
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3. Results and Discussion

Our retrosynthesis of 1 was based on a convergent process involving the Lewis acid-mediation of 3-alkoxyindoles 5 and 6 isomerization through an indolenium intermediate 4 as a key step (Scheme 1). Thus, the hydroxy group serves as a handle to direct isomerization reactions in a regioselective manner. The isomerization precursors 5 and 6 are obtained from 3-bromo-2-methoxyindole (ROBIN: 2-RO-3-bromoindoline) through silver-mediated alkoxylation. ROBIN is synthesized through the bromoetherification of a commercially available N-tosylindole (2) using NBS (N-bromosuccinimide) in MeOH [52].
Synthesis commenced from N-tosylindole (2) (Scheme 2). According to our previously developed protocol [48], ROBIN (2-RO-3-bromoindoline) was obtained in high yields. Next, silver-mediated alkoxylation of ROBIN with 1,2-propandiol as a nucleophile was conducted, generating desired alkoxyindoles 5 and 6 as a regioisomeric mixture (1.0:1.9) at an 80% yield. We observed that the regioisomeric ratio (5:6) ranged from 1.0:1.9 to 1.0:1.7 (See, Section 2, Section 2.3.1 and Section 2.3.3). This result suggested that the alkoxylation might be a reversible reaction, probably through possible intermediates such as a spiroketal intermediate [53,54] or an indolenium ion [55]. From the regioisomeric ratio (5:6), it was assumed that the isomerization step preferred a less-steric hindered nucleophilic attack by the 1° alcohol to steric-hindered nucleophilic attack by the 2° alcohol. To our knowledge, the isomerization of 3-alkoxyindoles has not been previously reported. Unfortunately, alkoxyindoles 5 and 6 could not be directly separated by preparative TLC and silica gel column chromatography. Thus, analytical samples of 5 and 6 were obtained after tert-butyldimethylsilyl (TBS) protection/separation by silica gel column chromatography (See, Section 2). The mixture of 5 and 6 was evaluated in a demethoxylative aromatization reaction without further purification. An initial screen of Brønsted acids resulted in decomposition, probably due to the presence of free alcohol. After intensive screening of Brønsted and Lewis acids (BF3•OEt2, AlCl3, ZnCl2, FeCl2, InCl3, InBr3, In(OTf)3, and Yb(OTf)3), we observed that BF3•OEt2 in AcOEt/MeCN generated the desired alkoxyindole 7 and 3 as a regioisomeric mixture (1.0:1.1) at a 50% yield [50]. The change in the diastereomeric ratio from 1.0:1.9 (5:6) to 1.0:1.1 (7:3) suggested that the demethoxylative aromatization of 5 and 6 occurred through cyclic intermediates such as a spiroketal intermediate 4′, which permitted the reaction through a stabilized oxonium ion. If the reaction proceeded as an acyclic intermediate [54], a less-steric hindered alkoxy exchange would be preferred. The undesired regioisomer 7 became separable after performing TBS protection/separation by silica gel column chromatography using 0.49 equiv. of TBSCl and 0.51 equiv. of imidazole to generate the secondary alcohol 3.
Next, we performed the detosylation of 3 to obtain N–H compound 1. Using NaOH-mediated detosylation, a trace amount of the desired N–H compound 1 was obtained due to its instability. In general, 1 displayed valuable stability to reaction conditions, which allowed us to determine more mild conditions. After intensive investigations, we found that tert-BuOK, which is a known steric hindered base, generated acceptable yields of the proposed structure 1 [56]. It was noteworthy that this detosylation tolerated the presence of free OH in 3.
The plausible mechanism of the isomerization of the mixture 5 and 6 is shown in Scheme 3. First, BF3•OEt2 promoted the elimination of an alcohol moiety (1,2-propandiol) which generated the common intermediate 4. Then, alkoxylation/demethoxylative aromatization occurred in the presence of 5 equivalents of BF3•OEt2 to generate the mixture 7 and 3 with the ratio of 1.0:1.1. This reaction proceeded through the intermediate 4′ due to an increase in the formation of sterically hindered 5.
The structure of 1-(1H-Indol-3-yloxy)propan-2-ol isolated from the Red Sea sponge Haliclona sp. was determined using NMR and HRMS data (Supplementary Material). A comparison of synthetic sample 1 1H and 13C NMR spectra with the literature revealed significant differences [49].
The largest 1H chemical shift differences were found for H2 (Table 1, synthetic 1: 6.80 ppm vs. reported 1: 7.95 ppm). The aromatic benzene region of the 1H chemical shift of our synthetic 1 was also different from reported 1 (synthetic 1: 6.95, 7.08, 7.25, and 7.57 ppm vs. reported 1: 7.16, 7.20, 7.45, and 8.13 ppm). Large 13C chemical shift differences were also observed for C2, C3, and C3a positions (Table 2, synthetic 1 (C2): 105.5 ppm vs. reported 1 (C2): 133.6 ppm; synthetic 1 (C3): 119.4 ppm vs. reported 1 (C3): 110.0 ppm; synthetic 1 (C3a): 140.1 ppm vs. reported 1 (C3a): 128.0 ppm). These key discrepancies in 1H and 13C NMR data potentially suggested an incorrectly determined indole ring system [6,57]. Unsurprisingly, misinterpretation of 1H and 13C NMR data is the most common reason for the misassignment of natural products [58,59,60,61,62,63,64]. To our surprise, we found that High-Resolution Mass Spectrometer (HRMS) data were also different (synthetic 1 vs. reported 1). In the isolation paper of 1, authors commented “Its high-resolution electron impact mass spectrometry (HREI-MS) showed an odd molecular ion peak at m/z 191.0946”. Molecular formula assignment is one of the critical steps in assigning a structure to an isolated natural product, and is based on matching isotopic composition to detected m/z values [65]. However, assignment can be interfered with by the complicated nature of peaks containing heteroatoms along with peaks containing heavy isotopes. Based on HRMS data differences between synthetic 1 [HRMS (ESI) m/z: 214.0844 (Calcd for C11H13NNaO2 [M + Na]+)] and reported 1 [HRMS (ESI) m/z: 191.0946 (Calcd for C11H13NO2 [M]+], a wrong heteroatom assignment might also occur [66]. Therefore, we suggest that the indolyl 1,2-propanediol alkaloid may be another heterocyclic compound.

4. Conclusions

We accomplished the first total synthesis of the proposed structure of an unprecedented indolyl saccharide alkaloid 1 bearing a 1,2-propandiol moiety. Isomerization of 3-alkoxyindolines through indolenium intermediates were key steps in the total synthesis. Our synthetic route was concise, requiring only five steps from N-Ts indole and yielding the target 1 at a 3% overall yield. 1H, 13C-NMR, IR, and HRMS spectra of the synthetic compound drastically differed to originally reported structure spectra. In the organic chemistry field, structural misassignments are problematic [66] and may be avoided using NMR chemical shift calculations [67] or machine learning [68,69]. A difficult task is to find the correct revision in the first place. Further synthetic studies to revise the natural product are ongoing in our laboratory.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/chemistry5040177/s1. The Supplementary Materials contain analytical data including Figures S1–S14: 1H- and 13C-NMR spectra.

Author Contributions

Conceptualization, T.A.; investigation, T.A.; resources, T.A.; visualization, T.A.; structures, T.A.; experiments, M.K.; writing—original draft preparation, T.A.; writing—review and editing, T.A. All authors have read and agreed to the published version of the manuscript.

Funding

This work was partly supported by JSPS KAKENHI (22K06503).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Conflicts of Interest

The authors declare no conflict of interest.

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Chemistry 05 00177 g001
Figure 1. Proposed structure of 1-(1H-Indol-3-yloxy)propan-2-ol (1) as the first indolyl 1,2-propandiol alkaloid.
Figure 1. Proposed structure of 1-(1H-Indol-3-yloxy)propan-2-ol (1) as the first indolyl 1,2-propandiol alkaloid.
Chemistry 05 00177 g001
Chemistry 05 00177 sch001
Scheme 1. Our retrosynthetic analysis for 1.
Scheme 1. Our retrosynthetic analysis for 1.
Chemistry 05 00177 sch001
Chemistry 05 00177 sch002
Scheme 2. Synthesis of proposed structure 1.
Scheme 2. Synthesis of proposed structure 1.
Chemistry 05 00177 sch002
Chemistry 05 00177 sch003
Scheme 3. Plausible isomerization mechanism.
Scheme 3. Plausible isomerization mechanism.
Chemistry 05 00177 sch003
Table 1. 1H-NMR data comparisons between synthetic and natural 1 samples.
Table 1. 1H-NMR data comparisons between synthetic and natural 1 samples.
Chemistry 05 00177 i011
PositionSynthetic 1
δH (mult, J in Hz)
600 MHz, methanol-d4		Natural 1
δH (mult, J in Hz)
500 MHz, methanol-d4
26.80 (s)7.95 (br s)
47.57 (ddd, 7.8, 1.2, 1.2)8.13 (br d, 7.8)
56.95 (ddd, 8.0, 7.2, 1.2)7.16 (dt, 7.6, 1.3)
67.08 (ddd, 8.1, 7.2, 1.2) 7.20 (dt, 7.6, 1.3)
77.25 (ddd, 8.4, 0.6, 0.6)7.45 (br d, 7.6)
83.90 (dd, 5.7, 0.6)3.44 (m)
94.17 (tq, 6.0, 5.4)3.80 (m)
101.30 (d, 6.0)1.15 (d, 6.4)
Table 2. 13C-NMR data comparisons between synthetic and natural 1 samples.
Table 2. 13C-NMR data comparisons between synthetic and natural 1 samples.
Chemistry 05 00177 i012
PositionSynthetic 1
δC
151 MHz, methanol-d4		Natural 1
δC
125 MHz, methanol-d4
2105.5133.6
3119.4110.0
3a140.1128.0
4117.1 122.2
5117.7122.1
6121.6123.4
7110.9112.8
7a134.5138.2
876.268.5
965.969.2
1018.419.6
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Kimata, M.; Abe, T. Total Synthesis of the Proposed Structure of Indolyl 1,2-Propanediol Alkaloid, 1-(1H-Indol-3-yloxy)propan-2-ol. Chemistry 2023, 5, 2772-2784. https://doi.org/10.3390/chemistry5040177

AMA Style

Kimata M, Abe T. Total Synthesis of the Proposed Structure of Indolyl 1,2-Propanediol Alkaloid, 1-(1H-Indol-3-yloxy)propan-2-ol. Chemistry. 2023; 5(4):2772-2784. https://doi.org/10.3390/chemistry5040177

Chicago/Turabian Style

Kimata, Momoko, and Takumi Abe. 2023. "Total Synthesis of the Proposed Structure of Indolyl 1,2-Propanediol Alkaloid, 1-(1H-Indol-3-yloxy)propan-2-ol" Chemistry 5, no. 4: 2772-2784. https://doi.org/10.3390/chemistry5040177

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